The onset of inflammatory bowel diseases (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is poorly understood, but appears to involve a combination of host susceptibility, environmental factors and aberrant response to the luminal microbiota of the gut. One of the hallmarks of IBD is the upregulation of the pro-inflammatory cytokine TNF in various cell types, including immune and intestinal epithelial cells (IECs) and anti- TNF interventions are used as IBD therapy. In spite of its clinical relevance, little is known about the in vivo factors controlling TNF expression. In a forward zebrafish genetic screen we found that loss of the epigenetic regulators Uhrf1 or Dnmt1 leads to de-repression of the tnfa locus in IECs and microbe-dependent intestinal inflammation that resembles human CD. Our proposed research addresses the central hypothesis that defects in epigenetic regulation can trigger IBD onset in via de-repression of TNF. We will use the zebrafish system to define transcriptional and post-transcriptional mechanisms regulating tnfa expression and function in the intestine and how these are influenced by microbiota. We will also investigate whether CD patients carry mutations in DNMT1 or UHRF1 that may lead to loss of promoter methylation and de-repression of the TNF locus. These studies are expected to yield new mechanistic insights into IBD onset and may facilitate new approaches for IBD diagnosis and therapy.